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Multicomponent reactions in the synthesis of nitrogen heterocycles and their application to drug discovery

MULTICOMPONENT REACTIONS
IN THE SYNTHESIS OF NITROGEN HETEROCYCLES
AND THEIR APPLICATION TO DRUG DISCOVERY
by
Alexey Butkevich
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(CHEMISTRY)
May 2011
Copyright 2011 Alexey Butkevich

This dissertation comprises two separate projects, relying on the use of multicomponent reactions as a common theme. The introduction (Chapter 1) briefly overviews the utility of multicomponent reactions highlighting their medicinal chemistry applications. The first part (Chapters 2 and 3) describes the development of new practical synthetic methodologies for one-step synthesis of nitrogen heterocycles (isoindolines and dihydroquinolines) using three-component reaction of boronic acids, amines and aldehydes (Petasis reaction) or its variations. The second part (Chapters 4 and 5) deals with the applications of multicomponent reactions to the diversity oriented synthesis of biologically active small molecules.; Chapter 2 reviews the known synthetic approaches to isoindoline derivatives based on [4+2] cycloadditions and describes the development of our own methodology based on tandem Petasis-Diels-Alder reaction, focusing on the expansion of the substrate scope (salicylaldehydes, heterocyclic aldehydes, glyoxylic acid, sugars and sugar ketals) and diastereoselectivity. Some transformations of the reaction products are also investigated.; Chapter 3 briefly overviews the known syntheses of 1,2-dihydroquinolines, discusses a new variation of catalytic version of Petasis reaction (2H-chromene synthesis, catalyzed by tertiary amines) and development of trifluoroborate-based approach to 1,2-dihydroquinolines. This methodology is further extended onto the novel trifluoroborate-based three-component reaction involving 2-sulfamidobenzaldehydes, simple aromatic and aliphatic aldehydes.; Chapter 4 includes a short review of classical Passerini and Ugi reactions from the mechanistic point, demonstrating the applicability of these reactions to the diversity-oriented synthesis of a wide variety of drug-like molecules. An insight is given into suggested biological mechanism of action of a series of 18 simple propiolamide pseudodipeptides, prepared in one step by Ugi reaction. Structure-activity relationship studies in a series of ~50 analogs prepared by Ugi reaction with some post-multicomponent step modifications are described, and preparation of fluorescent propiolamide-based tools for the identification of their intracellular targets is outlined. The reactions of propiolamides with biologically relevant nucleophiles are studied by NMR methods.; Chapter 5 describes the dual role of APE1/Ref-1 enzyme and briefly overviews a small number of known small molecule inhibitors. A set of ~20 diverse molecules aimed at selective targeting either its endonuclease or redox function is prepared using single-step multicomponent and multistep synthetic approaches.

MULTICOMPONENT REACTIONS
IN THE SYNTHESIS OF NITROGEN HETEROCYCLES
AND THEIR APPLICATION TO DRUG DISCOVERY
by
Alexey Butkevich
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(CHEMISTRY)
May 2011
Copyright 2011 Alexey Butkevich